Dimerization of the p185(neu) transmembrane domain is necessary but not sufficient for transformation
Dimerization of the p185(neu) transmembrane domain is necessary but not sufficient for transformation
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DOI：
10.1038/sj.onc.1200873
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发表时间：
1997-02-13
期刊：
影响因子：
8
通讯作者：
Stern, DF
中科院分区：
文献类型：
--
作者：
Burke, CL;Lemmon, MA;Stern, DF
neu原癌基因编码受体酪氨酸激酶（RTK）。致癌等位基因neu*（p185*）在预测的跨膜结构域内的位置664处携带谷氨酸替换为缬氨酸。我们已经使用这种突变体来探索跨膜结构域在RTK信号转导中的作用。一组在跨膜结构域中具有第二位点突变的neu* 蛋白的分析揭示了二聚化与转化的强烈相关性。二聚化和转化都依赖于由氨基酸Val 663-Glu 664-Gly 665（VEG）形成的结构域。然而，VEG在跨膜结构域内的其他位置的移动促进了弱二聚化，但不促进转化。表皮生长因子受体（EGFR）/neu嵌合体用于确定破坏Glu 664激活的突变是否也影响了EGFR调节的信号转导。这些突变（Val 663和Gly 665）不影响EGF的调节。从血型糖蛋白A（GpA）引入已知的跨膜二聚化结构域刺激二聚化，但不足以转化。这些结果表明，二聚化是必要的，但不足以转化活性。同源的野生型结构域，VVG，是不需要的酶调节信号。
The neu proto-oncogene encodes a receptor tyrosine kinase (RTK). The oncogenic allele neu* (p185*) bears a glutamic acid for valine substitution at position 664 within the predicted transmembrane domain. We have used this mutant to explore the role of the transmembrane domain in signal transduction by RTKs. Analysis of a panel of neu* proteins with second-site mutations in the transmembrane domain revealed a strong correlation of dimerization with transformation. Both dimerization and transformation are dependent on a domain formed by the amino acids Val663-Glu664-Gly665 (VEG). However, movement of the VEG elsewhere within the transmembrane domain promoted weak dimerization but not transformation, Epidermal growth factor receptor (EGFR)/neu chimeras were used to determine if mutations that disrupt activation by Glu664 affect hormone-regulated signal transduction as well. These mutations (of Val663 and Gly665) did not affect regulation by EGF, Introduction of the known transmembrane dimerization domain from Glycophorin A (GpA) stimulated dimerization, but was not sufficient for transformation. These results indicate that dimerization is necessary but not sufficient for transforming activity. The homologous wild-type domain, VVG, is not required for hormone-regulated signaling.